Cells of the innate immune system, such as monocytes, macrophages, natural killer (NK) cells, and polymorphonuclear neutrophils (PMN), are the first-line defenders against cancer and infectious disease by nature of their phagocytic, cytolytic, and antimicrobial properties. Monocytes and macrophages are believed to play an important role in inflammatory diseases through their activation and secretion of inflammatory mediators. For example, granulocyte macrophage-colony stimulating factor (GM-CSF) is known to promote proliferation and differentiation of granulocytes, monocytes, and macrophages. Granulocyte-colony stimulating factor (G-CSF) is known to promote the differentiation and growth of granulocytes and neutrophils (Ogawa, Blood 81:3844-2853 (1993)). At present, both G-CSF and GM-CSF are being used as protein therapeutics to promote the recovery of blood cells after chemotherapy, radiation, and bone marrow transplants.
NK cells are known to play a role in host responses to cancer. In both syngeneic and xenogenic transplant models, tumor cells grow more efficiently in NK−/− mice, and survival rates for the mice in these models are significantly less than those for mice possessing NK cells. In addition, potentiating an NK response with soluble protein factors, such as IL-2 or IL-15, has been shown to increase the efficiency by which NK cells kill tumor cells in the presence of anti-tumor antibodies both in vitro and in vivo (Carson et al., J. Exp. Med. 180:1395-1403 (1994)).
Additionally, NK cells are also known to play a role in host response to infectious disease. For example, mice lacking NK cells are known to have increased susceptibility to viruses and intracellular pathogens. Similarly, humans with naturally occurring NK cell deficiencies are also known to be highly susceptible to infections. In vitro, NK mediated killing of cells infected with virus or other intracellular pathogens is known to be potentiated by cytokines such as interferon-α, interferon-β, interleukin-12, and interleukin-18 (Wu et al., Adv. Cancer Res. 90:127 (2003)); Biron et al., Rev. Immunol. 17:189 (1999); Naume et al., Scand. J. Immunol. 40:128 (1994)).
It is also known that activated NK cells can be correlated with failure rates for women undergoing in vitro fertilization (IVF) procedures, and may be further linked to spontaneous pregnancy loss (Dosiou et al., Endocr. Rev. 26:44 (2005)). Additionally, elevated levels of activated NK cells may be found in a number of patients with immune endometriosis, one known underlying cause of infertility in women (Dosiou et al., Endocr. Rev. 26:44 (2005)).
Antigen-processing dendritic cells are capable of sensitizing T cells to both new and recall antigens. Dendritic cells express high levels of major histocompatibility complex class I and II antigens, which play a role in cancer immunotherapy, along with other immunomodulatory proteins, adhesins, and cytokines. Dendritic cell cancer vaccines have been reported to be produced by extracting a patient's dendritic cells and using immune cell stimulants to reproduce large amounts of dendritic cells in vitro or ex vivo. The dendritic cells can then be exposed to antigens from the patient's cancer cells. The combination of dendritic cells and antigens is injected into the patient, and the dendritic cells program the patient's T cells. Dendritic cells break down the antigens on the cancer cell surfaces, then display them to killer T cells. (Song et al., Yonsei Med. J. 45 Suppl.:48-52 (2004)).
Cancer patients recovering from autologous hematopoietic cell transplantation exhibit decreased levels of circulating dendritic cells. Dendritic cells develop from hematopoietic progenitors and promoting their development may help regain normal dendritic cell levels. The ability to generate dendritic cells by inducing proliferation of isolated human dendritic cells and inducing proliferation and differentiation of hematopoietic stem cells facilitates efficacy tests of dendritic cell vaccination and facilitates effective vaccination practice. There is a need in the art for factors that stimulate dendritic cell proliferation and/or hematopoietic stem cell proliferation and/or differentiation to dendritic cells. There is also a need in the art for factors that promote the generation of dendritic cells from hematopoietic cells to increase circulating dendritic cells in preparation for hematopoietic cell transplantation.
Osteoclasts share a common progenitor with dendritic cells, macrophages, and microglia (Servet-Delprat et al., BMC Immunol. 3:15 (2002)). These multinucleated, adherent, bone-resorbing cells differentiate in the bone marrow and function in the vicinity of the bone to regulate bone remodeling and calcium homeostasis. Osteoclast differentiation and function has been reported to be regulated by secreted factors, including M-CSF and osteoprotegerin (RANK ligand) (Miyamoto et al., Keio. J. Med. 52:1-7 (2003)). Factors which play a role in the regulation of osteoclast differentiation and function may be therapeutic in treating osteoporosis and other bone diseases.
Microglial cells function as immune effectors of the central nervous system, where they also produce neurotrophic factors and regulate glutamate uptake. These mononuclear phagocytes are distributed throughout the central nervous system parenchyma in both the white and grey matter. Microglia have been reported to be present in increased numbers in patients with Alzheimer's disease, wherein they display marked increases in nitric oxide production and inflammatory cytokines, including IL-1 and MIP1 alpha (Vincent et al. Neurobiol. Aging 23:349-362 (2002)). Factors that regulate microglial differentiation and function may be therapeutic in treating Alzheimer's disease and other neural diseases, including demyelinating diseases such as multiple sclerosis, acute disseminated encephalomyelopathy, progressive multifocal leukoencephalopathy, stroke, and Parkinson's disease.
Gene MGC34647 encodes the hypothetical protein NP—689669 (Strausberg et al., Proc. Natl. Acad. Sci. 99:16, 899 (2002)). The functions of this gene and its encoded polypeptides are previously unknown. The sequences of MGC34647 and NP—689669 correspond to SEQ ID. NOS.: 49 and 103, respectively, of WO 2002/048337. They correspond to the amino acid sequence of a secreted protein of unknown function and its coding sequence, respectively.